Submissions for variant NM_000384.3(APOB):c.5599C>T (p.Arg1867Trp)

gnomAD frequency: 0.00024  dbSNP: rs200583769

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000256267	SCV000322843	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/202 non-FH alleles
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454967	SCV000538325	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Several papers, no segs; ExAC: 0.04% (3/6614) Finnish chromosomes
Iberoamerican FH Network	RCV000256267	SCV000748124	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001837814	SCV000932478	likely benign	Hypercholesterolemia, autosomal dominant, type B; Familial hypobetalipoproteinemia 1	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001142490	SCV001302932	uncertain significance	Hypercholesterolemia, autosomal dominant, type B	2019-08-21	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001355072	SCV001776235	uncertain significance	not provided	2020-09-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#265887; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24234650, 26020417)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001355072	SCV004218693	uncertain significance	not provided	2024-04-03	criteria provided, single submitter	clinical testing	The APOB c.5599C>T (p.Arg1867Trp) variant has been reported in the published literature in an individual affected with familial hypercholesterolemia (PMID: 24234650 (2014)). The frequency of this variant in the general population, 0.0003 (10/33078 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Ambry Genetics	RCV004021039	SCV005034731	benign	Cardiovascular phenotype	2024-02-20	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355072	SCV001549841	uncertain significance	not provided		no assertion criteria provided	clinical testing	The APOB p.Arg1867Trp variant was identified in 2 of 130 proband chromosomes (frequency: 0.0154) from individuals with Familial Hypercholesterolaemia (Alves_2014_PMID:24234650). The variant was identified in dbSNP (ID: rs200583769), Cosmic and ClinVar (classified as a VUS by Laboratory for Molecular Medicine, Color, Iberoamerican FH Network and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). The variant was identified in control databases in 50 of 282636 chromosomes at a frequency of 0.000177 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 38 of 128992 chromosomes (freq: 0.000295), Other in 2 of 7214 chromosomes (freq: 0.000277), European (Finnish) in 4 of 25098 chromosomes (freq: 0.000159), Latino in 3 of 35434 chromosomes (freq: 0.000085), African in 2 of 24970 chromosomes (freq: 0.00008) and East Asian in 1 of 19948 chromosomes (freq: 0.00005), but was not observed in the Ashkenazi Jewish or South Asian populations. The p.Arg1867 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.